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    Clinical Trial Results:
    A randomised, double blind, placebo controlled crossover study of the influence of the HCN channel blocker ivabradine in a healthy volunteer pain model - an enriched population study

    Summary
    EudraCT number
    		 2012-005627-32
    Trial protocol
    		 GB  
    Global end of trial date
    07 Mar 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    17 Mar 2019
    First version publication date
    02 Apr 2017
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    The previous version the primary analysis wanted to model both the pre-capsaicin and post-capsaicin values. However empericially the pre-capsaicin were nearly all at the minimum value, with very little variability, which meant the model fitting was poor. A simpler model that only analyses post-capsaicin values is now used. This revised analysis corresponds to the result presented in the main study paper

    Trial information

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    Trial identification
    Sponsor protocol code
    IIVoP
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cambridge University Hospitals NHS Foundation Trust & University of Cambridge
    Sponsor organisation address
    Addenbrookes Hospital, Hills Road, Cambridge, United Kingdom, CB2 0QQ
    Public contact
    Carrie Bayliss, CCTU Cambridge University Hospitals NHS Foundation Trust, 44 1223348158, cctu@addenbrookes.nhs.uk
    Scientific contact
    Carrie Bayliss, CCTU Cambridge University Hospitals NHS Foundation Trust, 44 1223348158, cctu@addenbrookes.nhs.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    We examined whether ivabradine reduces the intensity of sensitisation induced by capsaicin. Application of capsaicin cream to the skin causes a reddening of the skin, and an increased sensitivity within the area the cream is applied (the primary hyperalgesia area) and in surrounding areas (the secondary hyperalgesia area). Changes in sensitivity can be assessed using quantitative sensory testing (QST). This will be an enriched population study, meaning that we will only include participants who respond to capsaicin. This was determined at the screening visit. The principle research objective was to investigate whether ivabradine reduces the area of secondary punctate mechanical hyperalgesia induced by capsaicin (a change in normal sensation to a von Frey hair or pin prick stimulator).
    Protection of trial subjects
    Blood pressure and heart rate monitoring was carried out during each visit and reviewed for safety before subjects were discharged from the clinical environment.
    Background therapy
    		 Capsaicin 0.5% cream; 1ml applied topically to alternating forearms
    Evidence for comparator
    		 The non-selective HCN channel blocking drug ivabradine is licensed for the symptomatic treatment of stable angina pectoris in patients with coronary artery disease and the treatment of heart failure. We recently investigated its effects on the symptoms of neuropathic pain in a smaller scale clinical trial (IISNeP) in 12 healthy volunteers (data not yet published). Results from this previous trial suggested that ivabradine may influence capsaicin-induced thermal and mechanical hyperalgesia, but this effect was of borderline statistical significance. However, in this initial trial there was variability in the size of the area of hyperalgesia that developed on the forearm between volunteers. The effect of ivabradine was greater in those participants who developed a large area of hyperalgesia (i.e. responded to capsaicin), providing strong justification for an enriched population trial of the influence of ivabradine on hyperalgesia in a group of capsaicin responders. This method of recruitment for experimental clinical studies using capsaicin has been previously reported due to the occurrence of capsaicin-responders and non-responders.
    Actual start date of recruitment
    01 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 55
    Worldwide total number of subjects
    55
    EEA total number of subjects
    55
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    55
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All subjects were recruited within the UK.

    Pre-assignment
    Screening details
    		 Area of capsaicin induced hyperalgesia on the screening visit was calculated to determine capsaicin-responders who proceed into the treatment phase of the trial. A capsaicin-responder was defined as someone who has an area of punctate hyperalgesia on the forearm equal to or greater than 20 cm(2), rounded to the nearest cm(2), at at 75 minutes.

    Pre-assignment period milestones
    Number of subjects started
    		 55
    Number of subjects completed
    		 27

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not fulfill screening criteria: 28
    Period 1
    Period 1 title
    Post Screening @ 0 mins (Baseline)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Subjects, researchers & statisticians were blinded to allocation to Investigational Medicinal Product (IMP). Placebo and active medication comparator were designed and manufactured to be visually indistinguishable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ivabradine First
    Arm description
    		 Subjects were randomised to Ivabradine first and Placebo second or to Placebo first and Ivabradine second in a cross over study.
    Arm type
    		 Crossover

    Investigational medicinal product name
    Ivabradine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    7.5 mg oral administration

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    placebo containing only excipients for oral administration (indistinguishable visually from ivabradine 7.5 mg film coated tablets for oral administration).

    Arm title
    		 Placebo First
    Arm description
    		 Subjects were randomised to either Ivabradine first or Placebo First in a cross over design study
    Arm type
    		 Crossover

    Investigational medicinal product name
    Ivabradine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    7.5 mg oral administration

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    placebo containing only excipients for oral administration (indistinguishable visually from ivabradine 7.5 mg film coated tablets for oral administration).

    Number of subjects in period 1 [1]
    		Ivabradine First Placebo First
    Started
    15
    12
    Completed
    12
    12
    Not completed
    3
    0
         Early closure of study
    1
    -
         Not contactable
    2
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: To progress beyond enrollment to randomisation, patients needed to undergo an assay to determine if they satisfy the inclusion criteria. 28 patients did not, leaving 27 who were randomised.
    Period 2
    Period 2 title
    Post Screening @15, 30, 45, 60 & 75 mins
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Ivabradine and Placebo tablets were formulated to be visually identically and indistinguishable.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Ivabradine
    Arm description
    		 Subjects were randomised to either Ivabradine first or placebo first sequences of IMP administration in a crossover design
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ivabradine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    7.5 mg oral administration

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    placebo containing only excipients for oral administration (indistinguishable visually from ivabradine 7.5 mg film coated tablets for oral administration).

    Arm title
    		 Within Patient Difference
    Arm description
    		 -
    Arm type
    		 Crossover Comparison

    Investigational medicinal product name
    Ivabradine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    7.5 mg oral administration

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    placebo containing only excipients for oral administration (indistinguishable visually from ivabradine 7.5 mg film coated tablets for oral administration).

    Number of subjects in period 2
    		Ivabradine Placebo Within Patient Difference
    Started
    24
    24
    24
    Completed
    24
    24
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ivabradine First
    Reporting group description
    		 Subjects were randomised to Ivabradine first and Placebo second or to Placebo first and Ivabradine second in a cross over study.

    Reporting group title
    Placebo First
    Reporting group description
    		 Subjects were randomised to either Ivabradine first or Placebo First in a cross over design study

    Reporting group values
    		 Ivabradine First Placebo First Total
    Number of subjects
    		 15 12 27
    Age categorical
    Adults aged between 20 and 64 years old
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 15 12 27
        85 years and over
    		 0 0 0
    Age continuous
    Age collected in years
    Units: years
        arithmetic mean (standard deviation)
    		 37.7 ± 13.5 31.2 ± 12.5 -
    Gender categorical
    Self attributed gender roles
    Units: Subjects
        Female
    		 9 8 17
        Male
    		 6 4 10

    End points

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    End points reporting groups
    Reporting group title
    Ivabradine First
    Reporting group description
    		 Subjects were randomised to Ivabradine first and Placebo second or to Placebo first and Ivabradine second in a cross over study.

    Reporting group title
    Placebo First
    Reporting group description
    		 Subjects were randomised to either Ivabradine first or Placebo First in a cross over design study
    Reporting group title
    Ivabradine
    Reporting group description
    		 Subjects were randomised to either Ivabradine first or placebo first sequences of IMP administration in a crossover design

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Within Patient Difference
    Reporting group description
    		 -

    Primary: Area of Punctate Hyperalgesia

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    End point title
    		 Area of Punctate Hyperalgesia
    End point description
    Within each patient and visit (Ivabradine or Placebo) the change from baseline to 75 minutes post application of capsaicin cream in terms of Area of punctate hyperalgesia, was calculated. Then the within-patient difference Ivabradine - Placebo was calculated.
    End point type
    Primary
    End point timeframe
    Outcome at 75 minutes compared
    End point values
    		 Ivabradine Placebo Within Patient Difference
    Number of subjects analysed
    24
    24
    24
    Units: cm (2)
        arithmetic mean (standard deviation)
    34.9 ± 15.0
    33.45 ± 15.3
    1.45 ± 11.7
    Statistical analysis title
    		 Hierarchical analysis
    Statistical analysis description
    Hierarchical analysis was carried out for this endpoint to account for intra subject correlation (repeated measures) and to provide for Ivabradine versus Placebo contrasts. Restricted Maximum Likelihood was used for purposes of inferences.
    Comparison groups
    Ivabradine v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.04
         upper limit
    		 10.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.5

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the onset of screening to last patient last visit
    Adverse event reporting additional description
    Information about adverse events were collected both during routinely scheduled visits as well when subjects opportunistically contacted the researchers.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    IIVoP Safety Population
    Reporting group description
    		 This population comprises all subjects who were exposed to any IMP

    Serious adverse events
    		 IIVoP Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 IIVoP Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 25 (24.00%)
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Pain in left knee
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    NONE
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